RU2634698C2 - Method for 6-(5-ethoxyhept-1-yl)bicyclo[3,3,0]octane-3-one synthesis, and composition containing it - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to a method for 6- (5-ethoxyhept-1-yl) bicyclo[3.3.0]octane-3-one synthesis as a racemic mixture which is used for the treatment of dihydrotestosterone-mediated disorders. The method comprises reaction of the first mixture containing 7,7-dichloro-4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptane-6-one and 6,6-dichloro-4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptane-7-one with acetic acid and zinc to form the second mixture containing 4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptane-6-one and 4-(5-ethoxyhept-1-yl)bicyclo[3.2.0] heptane-7-one, reaction of the said second mixture with trimethylsulfonium iodide to form the third mixture containing 2-(5-ethoxyhept-1-yl)spiro[bicyclo[3.2.0]heptane-6.2'-oxyrane] and 4-(5-ethoxyhept-1-yl)spiro[bicyclo[3.2.0]heptane-6,2'-oxyrane], and reaction of the said third mixture with Lewis acid to form 6-5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one. The invention also relates to a pharmaceutical composition containing 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one obtained as described above in the form of a racemic mixture prepared as described above.

EFFECT: method allows to obtain the desired product in good yield and purity suitable for use in a pharmaceutical composition.

10 cl, 2 dwg, 4 ex

Description

FIELD OF TECHNOLOGY

The invention generally relates to a method for synthesizing a chemical compound, such as a method for synthesizing 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one or 6- (5-methoxyhept-1-yl) bicyclo [ 3.3.0] octan-3-one.

BACKGROUND

The chemical compound 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one (also known as ethoxyheptylbicyclooctanone or ETHOCYN ^® ) is a non-steroidal compound that penetrates the dermis. A similar compound is CYOCTOL ™, or 6- (5-methoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. These compounds competitively inhibit the intercellular dihydrotestosterone receptor (DHT), binding to skin tissue fibroblasts, and have been investigated for the possibility of using medical disorders such as acne vulgaris, hirsutism, androgenetic alopecia, and keloid scars to treat mediated DHT.

The synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one is complex due to, for example, the bicyclic structure of the compound, which includes four chiral centers. Synthesis involves numerous reactions, some of which are expensive or dangerous. One reaction involves expanding the cycle using an ether solution of diazomethane, which is obtained from DIAZALD ^® (N-methyl-N-nitroso-n-toluenesulfamide) and an alcoholic solution of potassium hydroxide. A reaction involving diazomethane is highly toxic and dangerous due to its explosive potential. Methods for the synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one and derivatives are described in US Pat. No. 4,689,349 to Kasha et al. Methods for the synthesis of derivatives of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one (6- (5-methoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, or CYOCTOL ™) is also allegedly described in Mulzer et al., "Stereocontrolled synthesis of all eight stereoisomers of the putative anti-androgen cyoctol", Tetrahedron 60: 9599-9614 (2004).

SUMMARY OF THE INVENTION

A method for synthesizing a compound such as 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one or methoxyheptylbicyclooctanone from 3- (5-ethoxyhept-1-yl) cyclopentene or another starting material is proposed. Such a method involves the reaction of 3- (5-ethoxyhept-1-yl) cyclopentene with dichloro-ketene to form the first mixture containing 7,7-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6 -one and 6,6-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one. The first mixture is reacted with acetic acid and zinc to form a second mixture containing 4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one. The second mixture is reacted with trimethylsulfonium iodide to form a third mixture containing 2- (5-ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxiran]. The third mixture is reacted with lithium iodide to form 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the synthesis of 3- (5-ethoxyhept-1-yl) cyclopentene from 2-methylcyclohexan-1,3-dione; and

in FIG. 2 shows the synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one from 3- (5-ethoxyhept-1-yl) cyclopentene in accordance with an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A method for the synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one is proposed. The method according to the present invention provides a safer and less expensive way to obtain 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. The 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one synthesized by the method according to the invention can be obtained in good yield and have a purity suitable for use in a composition such as a drug or cosmetic composition.

As used herein, the terms “comprising,” “including,” “comprising,” “characterized,” and their grammatical equivalents are inclusive or non-limiting terms that do not exclude additional, unspecified elements or process steps, but also include narrower terms “consisting of” and “essentially consisting of” and their grammatical equivalents. As used herein with respect to a material, structure, characteristic or action according to a method, the term “may” indicates that they are intended to be used in carrying out an embodiment of the invention, and is preferably used in comparison with the narrower term “is” in order to avoid any hint that other compatible materials, structures, characteristics and methods applicable in conjunction with this should or should be excluded.

The compound 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can be synthesized as described in figures 1 and 2. In FIG. 1 describes the synthesis of 3- (5-ethoxyhept-1-yl) cyclopentene (Compound IX) from 2-methylcyclohexan-1,3-dione. In FIG. 2 shows the synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one from Compound IX.

As shown in Reactions 1 and 2 in FIG. 1, 2-methylcyclohexane-1,3-dione can react with sodium hydroxide and sodium borohydride in water to produce 5-hydroxyheptanoic acid (Compound IIA) and delta-lactone (Compound IIB) in a yield of from about 85% to about 105 % All percentages and ratios used herein are by weight of the total weight of the composition, unless otherwise indicated or the context otherwise. 2-methylcyclohexane-1,3-dione can be purchased from a chemical supply company, such as Sigma-Aldrich Co. (St. Louis, Missouri, USA). As a result of hydrolysis in Reaction 1, Compound I, a keto acid, is formed in high yield. The reduction of Compound I with sodium borohydride followed by quenching with acid gives a mixture of Compound IIA and Compound IIB, in which Compound IIB predominates. The carbonyl groups of Compound I can be reduced with sodium borohydride to form the resulting racemic mixture of the R and S enantiomers at the C5 position of Compound IIA and at the C6 position of Compound IIB.

Compounds IIA and IIB can react with triethylorthoformate (TEOF), ethanol, and sulfuric acid as a catalyst to produce ethyl 5-ethoxyheptanate (Compound III), as shown in Reaction 3. Both Compounds IIA and IIB react with these reagents to form single product, Compounds III. Compound III can be obtained in a yield of from about 50% to about 80%. Before further reactions, Compound III may be purified, for example, by distillation.

As shown in Reaction 4, Compound III can react with lithium aluminum hydride (PAH) in tetrahydrofuran (THF) to produce 5-ethoxyheptanol (Compound IV).

Compound IV can be obtained in a yield of from about 90% to about 99%. The reaction can be carried out at a temperature of from about -50 ° C to about room temperature (from about 20 ° C to about 25 ° C). In some embodiments, the reaction is carried out at room temperature to control the reaction. As shown in Reaction 5, Compound IV can be reacted with methanesulfonyl chloride (MsCl) and pyridine in dimethylformamide (DMF) to produce 1-chloro-5-ethoxyheptane (Compound V) in a yield of from about 75% to about 95%.

As shown in Reactions 6-8, Compound V can react with magnesium metal to form the Grignard reagent, 5-ethoxyheptyl magnesium chloride (Compound VI), which reacts with dilithium tetrachlorocuprate to form the dilithium cuprate complex. The dilithium cuprate complex can bind to 3-chlorocyclopentene (Compound VIII) to form 3- (5-ethoxyhept-1-yl) cyclopentene (Compound IX) in a yield of from about 55% to about 85%. Compound VIII can be synthesized from cyclopentene (Compound VII), which is synthesized from dicyclopentadiene, as shown in Reactions 6 and 7. Dicyclopentadiene can be purchased from a chemical supply company, such as Sigma-Aldrich Co. As a result of thermal cracking and distillation of dicyclopentadiene, monomeric cyclopentadiene is formed, which is treated with hydrochloric acid to obtain Compound VIII.

Each of Compounds I-IX in Reactions 1-8 can be processed, purified and isolated before proceeding to the next reaction. Compounds I-IX can be processed, purified and isolated by conventional methods, which are not described in detail here. In some embodiments, Compounds I-IX may be synthesized by the method described in US Pat. No. 4,689,349 to Kasha et al.

According to FIG. 2, Compound IX may be reacted with dichloro-ketene, as shown in Reaction 9. Dichloro-ketene is formed in situ from trichloroacetyl chloride and zinc. As a result of cycloaddition of dichloro-ketene to Compound IX, a mixture of exo- and endo-7,7-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and exo- and endo-6 6-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one, which together are referred to herein as Compound X. In Reaction 9, both isomers of Compound X are formed in substantially equal amounts. To obtain Compound X, Compound IX may be dissolved in an organic solvent, such as diethyl ether. However, other organic solvents can be used, for example dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran and any similar. Zinc powder may be added to the solution of Compound IX. From each mole of equivalent of Compound IX in Reaction 9, from about 1.0 mol to about 3.0 mol of equivalents of zinc powder can be used, for example, from about 1.4 mol of equivalents to about 1.8 mol equivalents. In certain embodiments, approximately 1.6 mol equivalents of zinc powder are used per mole of Compound IX equivalent. A mixture of zinc powder and a compound IX solution can be heated to a temperature slightly below the boiling point of the organic solvent. Trichloroacetyl chloride may be diluted with an organic solvent such as diethyl ether, and a trichloroacetyl chloride solution is slowly added to the mixture of zinc powder and a solution of Compound IX. However, other organic solvents may be used. For each molar equivalent of Compound IX in Reaction 9, from about 1.0 mol equivalents to about 3.0 mol equivalents of trichloroacetyl chloride, for example from about 1.2 mol equivalents to about 1.6 mol equivalents, can be used. In certain embodiments, approximately 1.4 mol equivalents of trichloroacetyl chloride are used per mol equivalent of Compound IX. During the addition process, the reaction mixture may begin to boil vigorously. A trichloroacetyl chloride solution can be added to the mixture of zinc powder and a solution of Compound IX over a period of from about one hour to about two hours. After adding a solution of trichloroacetyl chloride, the reaction mixture can be boiled with stirring for a period of time sufficient to complete the reaction, for example from about ten minutes to about sixty minutes. The reaction mixture can then be cooled, filtered, subjected to at least one liquid-liquid extraction, dried, filtered, evaporated and purified to give Compound X as a colorless oil. As an example, the reaction mixture may be cooled to room temperature and filtered through diatomaceous earth, such as kieselguhr, available under the trade name CELITE ^®. The filter cake may be washed with an organic solvent, such as, for example, diethyl ether. However, other organic solvents may be used. The layers of organic solvents can be combined and washed, for example, with water. The organic layer may be stirred with saturated aqueous sodium bicarbonate (NaHCO ₃ ), for example, for about one hour. After separation of the organic and aqueous layers, the organic layer can be washed with brine, dried over sodium sulfate (Na ₂ SO ₄ ), filtered through silica and evaporated in vacuo. The resulting residue can be purified, for example, by distillation from flask to flask to give Compound X as a colorless oil.

As shown in Reaction 10, Compound X can react with acetic acid and zinc to form a mixture of exo- and endo-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 4- (5-Ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one, which together are designated here as Compound XII. In Reaction 10, both isomers of Compound XII are formed in substantially equal amounts. Compound X can be used in Reaction 10 in an untreated form, that is, without distillation, which reduces the decomposition of Compound X. It is believed that heating Compound X to distill (to a temperature above 200 ° C) can cause it to decompose due to the presence of zinc or acid chloride remaining after Reaction 9. In Reaction 10, zinc can be added in portions to a solution of Compound X in acetic acid. An excess of zinc can be applied to Compound X. As an example, from about 2.0 mol equivalents to about 12 mol equivalents of zinc can be applied per mol equivalent of Compound X, for example from about 5 mol equivalents to about 10 mol equivalents. In certain embodiments, approximately 9.8 mol equivalents of zinc per mole equivalent of Compound X are used. Zinc may be added to a solution of Compound X at a temperature of from about 10 ° C to about 20 ° C. After the addition of zinc, which causes an increase in the reaction temperature, the reaction mixture can be stirred, for example, for about one hour. The reaction mixture can be filtered, evaporated, subjected to at least one liquid-liquid extraction, dried, filtered, evaporated and purified to give Compound XII as a colorless oil. As an example, the reaction mixture can be filtered through diatomaceous earth, such as kieselguhr, available under the trade name CELITE ^®, and the filtrate was evaporated in vacuo to give a residue. The resulting residue can be partitioned between heptane and water. The organic and aqueous layers can be separated and the organic layer washed with an aqueous solution of NaHCO ₃ . The organic layer can be dried over Na ₂ SO ₄ and an organic solvent, for example, such as diethyl ether, is added to it. However, other organic solvents may be used. The reaction mixture can be filtered, for example, using silica, and the filtrate is evaporated. The resulting residue can be purified, for example, by distillation from flask to flask to give Compound XII as a colorless oil. Compound XII can be obtained in a yield greater than about 55%. Compound XII is stable and may be distilled.

As shown in Reaction 11, Compound XII may react with trimethylsulfonium iodide to form 2- (5-ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxirane] and 4- (5 -ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxirane], which together are designated here as Compound XIII. In Reaction 11, both isomers of Compound XIII are formed in substantially equal amounts. Compound XIII is stable and can be isolated. Sodium hydride can be added to an organic solvent, for example dimethyl sulfoxide (DMSO), heated to a temperature of from about 50 ° C to about 60 ° C and cooled to room temperature. However, other organic solvents may be used. Sodium hydride can be used in Reaction 11 in an amount of from about 1 mol equivalent to about 3 mol equivalents per mol equivalent of Compound XII, for example in an amount of about 1.2 mol equivalents. THF or another organic solvent, after cooling, can be added to a sodium hydride solution cooled to -5 ° C. Trimethylsulfonium iodide can be added to a cooled solution of sodium hydride in one portion. Trimethylsulfonium iodide can be used in Reaction 11 in an amount of from about 1 mol equivalent to about 3 mol equivalents per mol equivalent of Compound XII, for example in an amount of about 1.2 mol equivalents. After removal of the cooling source, THF or another organic solvent may be combined with Compound XII. Compound XII and THF can be added to a solution containing sodium hydride and trimethylsulfonium iodide, whereby the temperature of the reaction mixture increases. The reaction mixture may be reacted with stirring for a period of time sufficient to allow the reaction to end, during which the temperature of the reaction mixture can rise to about room temperature. Water can be added to the reaction mixture, after which at least one liquid-liquid extraction, drying, filtering and concentration are carried out to give Compound XIII as a colorless oil. By way of example, the reaction mixture may be poured into water and extracted with an organic solvent such as heptane. The organic layers can be washed with water and brine. An organic solvent such as ethyl acetate can be added and the solution dried over Na ₂ SO ₄ . The solution can be filtered, for example, using silica, and the filtrate is evaporated to give Compound XIII as a colorless oil. Compound XIII can be obtained in a yield greater than about 90%.

As shown in Reaction 12, lithium iodide can be reacted with Compound XIII to give 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one as the main product. Due to the symmetry of the final product, both isomers of Compound XIII can interact with lithium iodide to form 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. Lithium iodide can be used in Reaction 12 in an amount of from about 1 mol equivalent to about 3 mol equivalents per mol equivalent of Compound XIII, for example in an amount of about 1.2 mol equivalents. According to the method of the invention, a racemic mixture of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can be obtained in good yield and purity. A solution of lithium iodide in THF can be added in portions to a solution of Compound XIII in THF. Also in Reaction 12, Lewis acids other than lithium iodide may be used. Also in Reaction 12, another organic solvent, such as DMSO or dichloromethane, may be used. Since the reaction is exothermic, the reaction mixture can be cooled to room temperature in an ice bath. The reaction temperature may vary from about 10 ° C to about 25 ° C. The reaction mixture may be stirred for a period of time sufficient to allow the reaction to complete, for example from about one hour to about three hours. After the reaction is complete, water can be added and the reaction mixture is subjected to at least one liquid-liquid extraction with an organic solvent, such as heptane. The organic layers can be washed with water, dried, filtered and purified to give 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one as an oil. As an example, water can be added to the reaction mixture and the reaction mixture is extracted with heptane. The organic layers can be washed with water and aqueous brine, dried over Na ₂ SO ₄ and filtered through silica. Silica can be washed with 20% ethyl acetate in heptane, which is concentrated to give 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one as an oil. The oil can be further purified by chromatography to give pure 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one with a yield of more than about 20%, for example more than about 40%. 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one may have a purity of more than approximately 99% according to chromatographic mass spectrometric (GC / MS) analysis. 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can have a purity of more than approximately 95% according to analysis by nuclear magnetic resonance (NMR) and more than 85% according to analysis when using chiral gas chromatography (GC).

A similar method can also be used to synthesize 6- (5-methoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, or CYOCTOL ™. CYOCTOL ™ is an ETHOCYN ^® derivative having a methoxy group at position C5 instead of an ethoxy group. CYOCTOL ™ can be synthesized in a manner analogous to that described above.

If further purification of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one is required, it can be carried out by conventional methods, for example, by chromatography.

Since 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one has four chiral centers, 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one synthesized according to the method of the invention can theoretically include up to sixteen different isomers. However, the two five-membered rings of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one are cis-fused since the two chiral centers C-3a and C-6a are linked to each other. Thus, according to the method of the invention, a racemic mixture of eight different isomers of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can be obtained.

In some embodiments, the chemical compound 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, prepared as described above, can be prepared as a composition suitable for topical use, for example, as pharmaceutical or cosmetic composition. As an example, 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can be prepared as a balm, cream, ointment, lotion, gel, foam, dispersion, mousse, solution, aerosol , suspensions or emulsions. 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can also be included in various cosmetic products, including, but not limited to, solid, semi-solid, liquid cosmetics (for example, a makeup base , eye cosmetics, lip care), makeup removers, deodorants and antiperspirants, soaps, bath and shower products (e.g. oils or salts), hair care products, sunscreen, shaving lotions and products for children . 6- (5-Ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one may also be formulated as a composition suitable for oral administration, for example, in the form of a tablet or capsule.

6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one may be present in the composition in a therapeutically effective amount, which is that amount of a compound which, if administered to a patient for treatment or prevention of a medical disorder or condition, is sufficient to carry out such treatment or prophylaxis. In certain embodiments, 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one may be present in the composition at a concentration of from about 0.01% by weight to about 5% by weight. 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one can be used to treat or prevent mediated DHT medical disorders such as acne vulgaris, hirsutism, androgenetic alopecia, or keloid scars.

The composition may also include a pharmaceutically acceptable binder, which may function as a diluent, dispersant or solvent. Pharmaceutically acceptable is a non-toxic, biologically acceptable, compatible with 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one and otherwise a biologically suitable binder for administration to humans. A pharmaceutically acceptable binder is added to the composition or otherwise used as a binder, carrier or diluent to facilitate administration of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. A pharmaceutically acceptable binder may include, but is not limited to, water, saline, phosphate buffer, Hanks's solution, Ringer's solution, dextrose in saline, or glucose, lactose, or sucrose solutions. The composition may also include pharmaceutically acceptable excipients such as starch, glucose, lactose, sucrose, gelatin, malt extract, rice flour, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water or ethanol.

The composition may optionally include small amounts of other ingredients, such as absorbents, abrasives, anti-caking agents, anti-foaming agents, antimicrobial agents, binders, biological additives, buffering agents, fillers, chemical additives, cosmetic biocides, methylated spirits, cosmetic binders, drug binders funds, external analgesics, film formers, matting additives, essential oils, irritants, emollients, funds, soothe skin, skin healing agents, plasticizers, preservatives, preservative enhancers, propellants, reducing agents, skin care products, skin penetration enhancers, skin protective agents, solvents, suspending agents, thickeners, solubilizers, sunscreens, anti-tanning agents, ultraviolet absorbing or scattering agents, artificial tanning agents, chelating agents, exfoliating agents, depilatory agents, exfoliating agents / exf lianty, organic hydroxy acid or natural extracts.

The following examples serve to explain in more detail the embodiments of the present invention. These examples should not be construed as exhaustive or limiting the scope of the present invention.

Examples

Solvents and reagents that were used in the synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one were purchased from commercial suppliers, for example, Sigma-Aldrich Co. (St. Louis, Missouri, USA) or other chemical supply companies. Solvents and reagents were used purity analytical grade. or higher.

Example I

Synthesis of Compound X from Compound IX

Zinc powder (17.5 g, 0.268 mol) was added to a solution of Compound IX (35.2 g, 0.168 mol) in diethyl ether (250 ml). The mixture was heated just below boiling point. Trichloroacetyl chloride (26.3 ml, 0.234 mol) was diluted with diethyl ether to 100 ml and this solution was added dropwise to a mixture comprising Compound IX. After about one minute, the reaction mixture began to reflux vigorously. Adding a solution of trichloroacetyl chloride took about ninety minutes. After the addition was completed, stirring was continued at the boil under reflux for approximately thirty minutes. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth, CELITE ^®. The filter cake was washed with diethyl ether. The combined organic layers were washed twice with water and the organic layer was stirred with saturated aqueous NaHCO _{3 for} about an hour. After separation of the layers, the organic layer was washed with brine, dried over sodium sulfate (Na ₂ SO ₄ ), filtered through a small layer of silicon dioxide and concentrated in vacuo. The resulting residue was purified by distillation from flask to flask (0.03 mm Hg, 180-200 ° C) with the release of approximately 45 g of a colorless oil.

Example II

Synthesis of Compound XII from Compound X

To a solution of Compound X (30 g, 0.093 mol) in acetic acid (250 ml) at a temperature of approximately 15 ° C, zinc (60 g, 0.91 mol) was added in small portions over a period of approximately forty-five minutes. The temperature has increased to approximately 25 ° C. After the addition was completed, the mixture was stirred for approximately one hour. The reaction mixture was filtered through diatomaceous earth, CELITE ^® and the filtrate concentrated in vacuo. The resulting residue was partitioned between heptane and water. The organic and aqueous layers were separated and the organic layer was washed twice with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and 50 ml of ethyl acetate was added thereto. The mixture was filtered through silica and the filtrate was concentrated. The resulting residue was purified by distillation from flask to flask (0.02 mm Hg, 140 ° C) with a yield of approximately 14.5 g of a colorless oil (0.0575 mol, yield 62%).

Example III

Synthesis of Compound XIII from Compound XII

NaH (2.7 g, 60% in oil, 67.4 mmol) was added to DMSO (100 ml). The mixture was heated to 55 ° C and stirred for approximately 1.5 hours. After the mixture was cooled to room temperature, THF (100 ml) was added and the mixture was cooled to -5 ° C. Trimethylsulfonium iodide (13.7 g, 67.4 mmol) was added in one portion and the mixture was stirred for approximately two minutes, during which the trimethylsulfonium iodide was not completely dissolved. The ice-methanol bath was removed and a solution of Compound XII (14.15 g, 56.15 mmol) in THF (20 ml) was added in one portion. The temperature rose to about 8 ° C. Stirring was continued for approximately two hours and the temperature was allowed to rise to room temperature. The mixture was poured into water (500 ml) and extracted twice with heptane (2 × 300 ml). The combined organic layers were washed four times with water and once with brine. Ethyl acetate (200 ml) was added and the solution was dried over Na ₂ SO ₄ . The mixture was filtered through a small pad of silica and concentrated to 14.8 g (0.0556 mol, 99% yield) of Compound XIII as a colorless oil.

Example IV

Synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one from Compound XIII

To a solution of Compound XII (47.2 g, 0.177 mol) in THF (200 ml) was added portionwise a solution of lithium iodide (28.5 g, 0.212 mol) in THF (100 ml). The addition was very exothermic, the reaction mixture was cooled to room temperature in an ice bath. The reaction temperature ranged from about 10 ° C to about 25 ° C. The mixture was stirred for approximately two hours and poured into water (200 ml). The mixture was extracted twice with heptane. The combined organic layers were washed twice with brine, dried over sodium sulfate (Na ₂ SO ₄ ) and filtered through silica. The silica layer was washed with a 20% solution of ethyl acetate in heptane. The organic layers were concentrated to give approximately 45 g of crude product as an oil. The crude product was purified by chromatography (gradient 0-25% ethyl acetate in heptane, silicycle cartridge 800 g Si) to give approximately 22 g (0.082 mol, 46% yield) of pure 6- (5-ethoxyhept-1-yl) bicyclo [3.3 .0] octan-3-one. Another fraction of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, approximately 11 g, was obtained in a lower purity (23% yield).

Although the invention may be subject to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and have been described in detail here. However, it should be understood that the invention should not be limited to the specific disclosed forms. On the contrary, the invention should cover all modifications, equivalents and alternatives falling within the scope of the invention, as defined by the following claims and their legal equivalents.

Claims (16)

1. The method of synthesis of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one in the form of a racemic mixture, including: the reaction of the first mixture containing 7,7-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 6,6-dichloro-4- (5-ethoxyhept-1-yl ) bicyclo [3.2.0] heptan-7-one, with acetic acid and zinc to form a second mixture containing 4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 4- ( 5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one; the reaction of said second mixture with trimethylsulfonium iodide to form a third mixture containing 2- (5-ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxiran] and 4- (5-ethoxyhept-1 -yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxiran]; and reacting said third mixture with a Lewis acid to form 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. 2. The method according to p. 1, characterized in that the reaction of the first mixture with acetic acid and zinc with the formation of the second mixture includes the reaction of the specified first mixture with acetic acid and zinc without distillation of the first mixture. 3. The method according to p. 1, characterized in that the reaction of said second mixture with trimethylsulfonium iodide to form a third mixture comprises adding trimethylsulfonium iodide, sodium hydride and dimethyl sulfoxide to said second mixture. 4. The method according to p. 1, characterized in that the reaction of the specified third mixture with Lewis acid with the formation of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one involves the dissolution of these 2- (5 -ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxirane] and 4- (5-ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2 ' -oxirane] in tetrahydrofuran and the addition of a solution of lithium iodide in tetrahydrofuran. 5. The method according to p. 1, characterized in that the reaction of the specified third mixture with Lewis acid with the formation of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one includes filtering and concentrating the specified 6- (5-Ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. 6. The method of claim 1, further comprising purifying said 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one. 7. The method according to p. 1, characterized in that the reaction of said third mixture with a Lewis acid involves the reaction of said third mixture with lithium iodide. 8. The method according to p. 1, characterized in that the reaction of the first mixture with acetic acid and zinc involves the reaction of zinc with the indicated 7,7-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptane- 6-one and 6,6-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one in a solution of acetic acid. 9. The method according to p. 1, characterized in that the reaction of the specified second mixture with trimethylsulfonium iodide includes the reaction of the specified second mixture with trimethylsulfonium iodide and sodium hydride. 10. A pharmaceutical composition for treating dihydrotestosterone-mediated disorders, comprising an effective amount of a 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one racemic mixture, wherein said 6- (5-ethoxyhept- racemic mixture 1-yl) bicyclo [3.3.0] octan-3-one is obtained by a method including: the reaction of the first mixture containing 7,7-dichloro-4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 6,6-dichloro-4- (5-ethoxyhept-1-yl ) bicyclo [3.2.0] heptan-7-one with acetic acid and zinc to form a second mixture containing 4- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-6-one and 4- (5 ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one; the reaction of said second mixture with trimethylsulfonium iodide to form a third mixture containing 2- (5-ethoxyhept-1-yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxiran] and 4- (5-ethoxyhept-1 -yl) spiro [bicyclo [3.2.0] heptane-6,2'-oxiran]; and reacting said third mixture with a Lewis acid to form 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one.

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